A method of preparing N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine, a known leukotriene B4 receptor antagonist, is known (Lee, Sung-eun, Synthesis and Biological Activity of Natural Products and Designed New Hybrid Compounds for the Treatment of LTB4 Related Disease, Ph.D thesis, Graduate School of Busan Univ., August 1999).
The preparation method of N-hydroxy-4-{5-[4-(5-isopropyl-2-methyl-1,3-thiazol-4-yl)phenoxy]pentoxy}benzamidine disclosed in the above literature includes preparing a compound (6) (Reaction 1 below), preparing a compound (9) (Reaction 2 below) and then reacting the compound (6) with the compound (9), to give an object compound (Reaction 3 below).

In Reaction 1, anisole (2) is reacted with isovaleryl chloride to afford a compound (3), which is then reacted with tetra-n-butylammoniumtribromide, thus preparing 2-bromo-1-(4-methoxy-phenyl)-3-methyl-butan-1-one (4) (yield: 77%). The above compound (4) is reacted with thioacetamide, to prepare a compound (5). The compound (5) is reacted with aluminum chloride using an ethanethiol and methylene chloride (1:1) solvent, therefore giving an intermediate compound (6) (yield: 79%).
However, tetra-n-butylammoniumtribromide (4) used in the above reaction is disadvantageous because it drastically decreases the preparation yield, and is expensive and difficult to handle and thus unsuitable for use in mass production. In addition, ethanethiol, which is a solvent used in the preparation of the intermediate compound (6), causes offensive odors, and has shortcomings making it unsuitable for use in mass production methods.

In Reaction 2, 4-hydroxy-benzonitrile (7) is reacted with 1-bromo-5-chloropentane to afford a compound (8), after which the compound (8) is reacted with sodium iodide, thus obtaining an intermediate compound (9) having an iodine group substituted for a chlorine group (yield: 89%).
However, the above process is disadvantageous because the preparation of the intermediate compound (9) requires two processes. Therefore, there is the need to improve the economy of the above process for mass production.

In Reaction 3, the compound (6) prepared through Reaction 1 and the compound (9) prepared through Reaction 2 are reacted with sodium hydride, giving a compound (10) (yield: 94%). Subsequently, the compound (10) is reacted with hydroxylamine hydrochloride and sodium hydroxide, thus preparing a final compound (1) (yield: 83%).
As such, sodium hydride, which serves as an acid reactor in the above reaction, is difficult to handle and unsuitable for use in mass production. Further, purification is conducted using column chromatography, which is difficult to apply to mass production, and also, the yield is decreased (total yield: about 24%).
Therefore, the present inventors have studied economical preparation methods, which have simple reaction processes and a drastically increased preparation yield, and are suitable for mass production, thus completing the present invention.